KR20200043972A - Implants for prostheses and surgical treatment of damaged nerve tissue, using porous polytetrafluoroethylene - Google Patents

Abstract

The present invention relates to medicine and can be used in neurosurgery, traumatology, neurology, rehabilitation, and the like.
The aim of the claimed group of inventions is to develop an implant suitable for the treatment of various types of damaged nerve tissue in any period of severe trauma to the nerve tissue, especially the spinal cord, immediately after stopping a significant dysfunction to restore initial and stable conduction in the acute phase. And to reduce and prevent the dehydration process. The technical result of solving this problem is to provide the ability to restore damaged nerve tissue in large quantities.
This problem is solved using an implant for prosthetic damaged nerve tissue containing a porous material. The porous material is a porous polytetrafluoroethylene (PTFE) having a surface-volume structure uniformly distributed in the open pores and the inner surface of the open pores and including dead-end pores. The pore size is randomly distributed in the range of 150-300 microns.
Methods of treating damaged nerve tissue and the use of porous PTFE are also claimed to produce implants for damaged nerve tissue prostheses.

Description

Implants for prostheses and surgical treatment of damaged nerve tissue, using porous polytetrafluoroethylene

The present invention relates to medicine and can be used in neurosurgery, traumatology, neurology, rehabilitation, and the like.

A method of treating traumatic injuries of the spinal cord [1] is to implant the intercostal nerve into the damaged spinal cord. However, this method has little clinical effect. It has been found that the axons of the central nervous system (hereinafter referred to as the central nervous system) can undoubtedly regenerate in such implants, but cannot extend outside the implant to restore communication with neurons in other central nervous systems. Regenerative neurons become trapped on the implant side due to the formation of collagen scars. A method [2] of inserting a piece of embryonic tissue between the center and the periphery of the damaged spinal cord is known. Experimental studies have shown that when embryonic spinal cord slices are implanted, the length of the axons (ie 1-1.5 cm) is the most prominent, and cannot be considered a sufficient method. The axons of the inmates at the distal end of the implant do not grow and become trapped in the scar.

There is a method of treating spinal cord injury by placing a container containing Schwann cells covered with a special gel between the damaged spinal cord peripherals. Schwann cells obtained from human or rat peripheral nerve explants are cultured to significantly increase the number of cells. The cells are then placed in a matrix filling a semi-permeable tube. The semipermeable tube is located between the cut end (peripheral) of the spinal cord. The result of most transplantation of Schwann cells is that most of the axonal regeneration of the central nervous system, expansion through implants (emergence). However, axons were unable to form new neuronal connections by leaving the microenvironment in Schwann cells and reintroducing into the spinal cord tissue [3].

Therefore, the above known method cannot be used to effectively restore the function of the spinal cord as it cannot overcome collagen (binding) scars during axon growth. Axons cannot grow beyond the implant to reconnect with other neurons in the central nervous system. Regenerative neurons are attached to the implant.

In addition, according to the method described above, fragments of human tissue are used as implants, which can cause rejection and increase the risk of infection transmission.

The most suitable implants and methods of treating spinal cord injuries according to patent [4] are as follows: porous titanium tubes are described as implants, the inner and outer surfaces of which have at least one porous layer, the pores having a depth of 1 to 3 μm And less than 0,5 microns in diameter. The diameter of the tube depends on the diameter of the nerve to be treated.

The treatment is to put the damaged nerve in a tube.

The disadvantage of the present technology solution is that the axon diffusion region is only a porous layer on the inner surface of the tube, which leads to a limited number of restored nerve connections.

In addition, in order to place the damaged nerve in the described implant, the damaged nerve must be separated from the surrounding tissue. This is not possible in all parts of the body's nerve tissue. In particular, the described implant does not apply to the spinal cord and other areas within all periods of severe trauma shortly after alleviating major dysfunction. This function should prevent or reduce the dehydration process and contribute to the initial and stable restoration of conductivity in the acute phase.

The purpose of the claimed invention group is the treatment of various types of nerve tissue (especially spinal cord tissue) injuries at some time immediately after alleviating critical dysfunction to stably restore nerve conduction early in the acute phase and prevent and reduce the process of dehydration excess. It is to create a suitable implant. The technical result of solving this problem is to provide the ability to restore damaged nerve tissue in large quantities.

This problem is solved using an implant for prosthetic damaged nerve tissue containing a porous material. The porous material is a porous polytetrafluoroethylene (hereinafter referred to as PTFE) having an open pore and a surface-volume structure uniformly distributed on the inner surface of the open pore and including dead-end pores. The pore size is randomly distributed in the range of 150-300 microns.

Neural tissue can be spinal cord tissue or auditory nerve or optic nerve.

If the nerve tissue injury is a collagen scar to be partially destroyed or incised or excised, the implant is made in the form of a plate to replace the missing nerve tissue.

If the nerve tissue injury is necrosis of the neural tissue region, the implant can be made in the form of a split sleeve to cover the region of the necrotic nerve tissue.

The solution to this problem is reflected in the following method. In surgical methods for treating damaged nerve tissue, an implant for prosthesis of damaged nerve tissue containing a porous material is used. The porous material is a porous polytetrafluoroethylene having an open pore and a three-dimensional surface-volume structure uniformly distributed on the inner surface of the open pore and including dead-end pores. The pore size is randomly distributed in the range of 150-300 microns.

Damaged nerve tissues such as spinal cord tissues, auditory nerves, and optic nerves can be treated.

If the nerve tissue injury is a destroyed nerve tissue, nerve tissue rupture or collagen scar to be excised, the implant is made in the form of a plate and is placed in place of the missing fragment of the nerve tissue or in the area of the excised collagen scar.

If the nerve tissue injury is necrosis of the nerve tissue area, the implant is made in the form of a split sleeve and placed over the necrotic nerve tissue area.

This problem is solved by using the porous polytetrafluoroethylene according to claim 1 for the manufacture of implants for prostheses of damaged nerve tissue.

The invention is presented by way of example in the following non-limiting drawings.
1 is a schematic diagram of a first embodiment of a claimed implant.
2 is a schematic diagram of a second embodiment of the claimed implant.
3 to 6 show images of spinal cord fragments for Example 1.
7 to 11 show images of spinal cord slices for Example 2.

The claimed implant can be prepared, for example, by the method described in [5]. The implant is made of porous PTFE by mixing granules of the starting material with blowing agent granules (table salt), pressing the resulting mixture, washing the table salt in the resulting porous molded body and subsequent sintering. In this case, the composite structure of the pores is provided by the form of crushed granules of pore former. The dimensions of the dead end pores are determined by the particle size of the fine fraction of the blowing agent, and the dimensions of the open pores are determined by the particle size of the large fraction of the blowing agent.

The requested surgical treatment method for spinal cord injury is as follows.

Patients with spinal cord injury are diagnosed with nuclear magnetic resonance imaging (hereinafter referred to as NMR) of the spinal cord. The location and size of spinal cord defects, the presence of cysts and adhesions are determined. Based on the above data, one plate of a spinal cord implant (Fig. 1) of a specific size and shape made of a porous PTFE plate made in advance and having a specific aspect ratio is cut. The plate is sterilized and stored in a sterile package. The porous structure of the implant may be saturated with drugs or nerve tissue growth stimulants.

The patient was laid on his side and had a typical hysterectomy and opened the meninges. In the case of a 3.5-fold increase, meningeal-driven decomposition is performed by exposing the distal and proximal ends of the damaged spinal cord region. Collagen (connective tissue) scars are excised.

The prepared plate 1 of the implant is placed to fill the space between the periphery at the site of injury to the patient's spinal cord. The surgical wound is tightly closed in layers.

Surgical treatment methods for necrotic damage, such as the auditory nerve, are performed as follows.

In this case, the shape of the implant is selected in the form of a split sleeve 2 (2 degrees). During surgery, the necrotic portion of the nerve is opened to allow access to the non-necrotic nerve portion and the diameter of the split sleeve 2 of the implant is selected to adhere to the non-necrotic nerve portion.

The length of the split sleeve 2 of the implant is selected to be longer than the damaged area. Open the split sleeve 2 of the implant and capture the unnecrotic end to cover the necrotic portion of the nerve. The surgical wound is closed.

To evaluate the feasibility and effectiveness of the claimed device, tests were performed on the animals presented in the following examples.

Example 1

Surgery was performed in which the spinal cord of the dog in the T11 segment was cut in half, and the implant in the form of a porous PTFE plate according to the invention was implanted into the injury area. Restoration of motor activity in experimental animals was recorded.

Three months after surgery, spinal cord fragments and intact animal spinal cord fragments were extracted at the site of contact with the implant. Figures 3-6 show (x400) the results of studying the spinal cords of intact (a) dogs and experimental dogs (b). .

Materials and methods

The material under study was a piece of dog spinal cord in the region with the implant. After extraction (June 9, 2016), the material under test was placed on ice.

The fragments were divided into groups according to morphological studies.

Step 1. Hematoxylin-eosin staining (general histology).

Staining according to stage 2 Newsle (visualization of neuronal tissue elements)

Micro drug studies and micrograph preparations were performed using software, a computer, Leica digital camera, MPV-2 light microscope (manufactured by Leitz, Germany).

At the optical level, morphological changes were evaluated.

A database containing the results of morphological studies was formed using MS Excel. Statistical analysis of the results was performed using the program STATISTICA 6.1 (StatSoft).

3A shows a spinal cord fragment from the intact dog's thoracic spine (T11); Figure 3α shows a cross section of the spinal cord section 3 months after the half cut, fracture and 45 ⁰ angle of the PTFE implant placed at the thoracic spine (T11). Processed with hematoxylin-eosin (X400).

3B, reconstruction of the spinal cord structure is observed at the position where the PTFE is placed. The nerve grows into the pores of the implant, indicating recovery of nerve impulses at the incision site. No hypertrophy of connective tissue or formation of coarse collagen scars is observed.

Measurement of the activity of acetylcholinesterase can assess the presence of a mediator of acetylcholine, which occurs during cholinergic (parasympathetic) neurons. The final product of the reaction resulting from the participation of the acetylcholinesterase enzyme was determined in the form of a copper ferrocyanide precipitate that stains cholinergic nerves such as nerve fibers, peripherals, etc. in brown (4a-4α or nerves are shown in black) .

The cholinergic nerve distribution at the site of spinal cord injury recovers more slowly, as evidenced by lower aceticcholinesterase activity in nerve fibers regenerated in PTFE implanted in the damaged area of the spinal cord compared to the injured spinal cord site. The decrease in activity of aceticolinesterase is due to the development of much smaller regenerative nerves in the injured area than in the intact area.

In the experiment, a histochemical method was applied to detect cytoplasmic enzymes characterized by metabolic activity of cells, succinate and lactate dehydrogenase (LDG and SDG). The presence of enzymes in the dog's spinal cord is manifested by dark blue formazan deposits formed during the reduction of the tetrazolium salt (the main areas are the mitochondrial lining, outgoing criss, and cytoplasmic nets). Enzyme activity was evaluated by the optical density of the reaction product in the cytoplasm of the cells (Formazan) using an Image J computer data processing program, and 100 cells were considered in 5 sections.

5A and 5B show the detection of lactate dehydrogenase in neurons and nerves of the spinal cord (nerve shown in black). A comparative analysis of the histochemical data obtained by measuring the average activity of LDG in the nerves of the spinal cord at the site of PTFE damage and above and below the damage showed that the activity of LDG enzyme at the site of injury increased significantly by 54% and 50%, respectively. This reaction accelerates the repair process of nerve tissue.

6A and 6B show succinate dehydrogenase discovery in neurons and vertebral nerves (nerve shown in black). A comparative analysis of histochemical data obtained by measuring the average activity of SDG at the nerve periphery of the spinal cord at the site of PTFE damage and above and below the injury showed that the activity of LDG enzyme at the site of injury increased significantly by 57% and 52%, respectively. .

Based on histology (stained with hematoxylin and eosin), neurohistology (stained with Newsled) and histochemistry studies (observing the activity of AChE, LDG and SDG), the following conclusions can be drawn:

PTFE 배치 위치에 연구된 척수 영역 구조의 재구성이 관찰되었다 (3α도). 신경이 임플란트된 PTFE에 걸쳐 임플란트의 기공에 생겨나고, 이는 절개 영역에서 신경 자극의 전도성을 회복시킨다. 결합 조직의 비대 (콜라겐 흉터)는 관찰되지 않았다.

Reconstruction of the structure of the spinal cord region studied at the PTFE placement site was observed (3α degrees). Nerves are created in the pores of the implant over the implanted PTFE, which restores the conductivity of the nerve impulses in the incision area. Hypertrophy of the connective tissue (collagen scars) was not observed.

척수의 뉴런은 척수의 인접한 온전한 영역에서 전체 부피에 이식된 PTFE의 기공, 손상 부위에 활발하게 재생된다.

Neurons in the spinal cord are actively regenerated in the pores and damaged areas of the PTFE implanted in the entire volume in adjacent intact areas of the spinal cord.

척수의 손상된 부위에 이식된 PTFE에서 재생되는 뉴런은 척수의 기능적 활동을 회복시킨다. 이는 재생 신경에서 에너지 대사 효소-LDG 및 SDG의 활성 지표가 크게 증가한 것으로 입증된다.

Neurons regenerated from PTFE implanted in the damaged area of the spinal cord restore the functional activity of the spinal cord. This is evidenced by a significant increase in the activity indicators of energy metabolizing enzymes-LDG and SDG in regenerative nerves.

척수 절반 절개가 없거나 실험 손상 부위에 PTFE 임플란트를 배치한 후 개의 척수 샘플에서 생존 세포의 백분율 사이체 유의미한 차이가 검출되지 않았다.

There was no significant difference between the percentages of viable cells in the spinal cord samples of dogs after half of the spinal cord incisions or after placing the PTFE implant at the site of the experimental injury.

실험 손상 부위에 온전한 개 및 PTFE 임플란트 배치 후 개의 척수 부분에서 CD90 (줄기 세포 마커)의 조직화학적 발현 지수의 계산에 유의한 차이가 없었다.

There was no significant difference in the calculation of the histochemical expression index of CD90 (stem cell marker) in the spinal cord area of the dog after placement of the intact dog and PTFE implant at the site of the experimental injury.

Example 2

The purpose of this study was the spinal cord of rats divided into 3 groups. Group 1-intact rats (control), group 2-rats undergoing partial incision of the spinal cord, group 3-rats receiving a partial incision of the spinal cord and transplanted with PTFE synthetic material to the site of injury. The observation period is 2 months.

Work includes histological (staining with hematoxylin and eosin), neurohistological (staining according to Newsle) and histochemical research methods (acetylcholinesterase, lactate and succinate dehydrogenase (AChE, LDG, SDG) (Indicating the activity of).

Cryogenic spinal cord sections of the spinal cord are stained with hematoxylin, eosin and toluidine blue and studied at the optical level.

7A shows the spinal cord portion of the intact rat thoracic spine (T11). Processed with hematoxylin-eosin (X400).

7B shows a cross section of the rat spinal cord after half incision and destruction of the thoracic vertebra (T11) without implant placement. Processed with hematoxylin-eosin (X400). Glial capsules, where the glial cells (mainly astrocytes) located in the form of a multi-layered shaft form a wall, are formed along the edges of the scar tissue (shown in black in the drawing) color, rough connective tissue scars). There are degenerative changes in the glial cells found in the adjacent areas of the spinal cord. Hemodynamic disorders in adjacent areas of the spinal cord material are found due to necrotic changes in the walls of blood vessels, leakage of the liquid part of the blood into the intravascular space and the development of arterial hematoma. Vacuuming and edema of the cytoplasm, destruction of some cells (white voids) is observed.

FIG. 7C shows a cross-section of the spinal cord of the rat after destruction of the half incision and thoracic spine (T11) and placement of the ^PTFE implant at an angle of 450 degrees. Processed with hematoxylin-eosin (X400). Light gray area-PTFE.

In the area investigated, loose connective tissue scars were found and there were newly formed blood capillaries within the scars. It represents active angiogenesis in scar tissue. A number of neurons with long peripherals and astrocytes that have spread and do not form glial cell boundaries that prevent regeneration of nerve tissue along the periphery of the scar are also observed. Hematoxylin-eosin processing (X400)

Measurement of the activity of acetylcholinesterase can assess the presence of a mediator of acetylcholine, which occurs during cholinergic (parasympathetic) neurons. The final product of the reaction resulting from the participation of the enzyme acetylcholinesterase is determined by the brown precipitated form of copper ferrocyanide, which browns the cholinergic nerves such as nerve fibers and peripherals.

8A shows the spinal cord portion of the intact rat thoracic spine (T11).

8B shows a part of the spinal cord of the rat after incision and destruction of the thoracic vertebra (T11) in half without implant placement. Rough destruction of nerve fibers and uneven accumulation of enzymes in neurons (absence) were observed. Acetylcholinesterase activity is reduced.

8C shows a cross-section of the spinal cord of a rat after destruction of the half incision and thoracic spine (T11) and placement of a ^PTFE (PTFE gray and black) implant at a 450-degree angle. The activity of the acetylcholinesterase enzyme in nerve fiber regeneration is higher than that of the rat group without implant placement.

9A-9C show spinal cord cross sections of rats stained according to Nissl (visualize only elements of neuronal tissue, dark blue (indicated in black) -neurons and peripherals) (X400).

9A shows the spinal cord portion of the thoracic (T11) region of an intact rat.

9B shows part of the spinal cord of the rat after incision and destruction of the thoracic vertebra (T11) in half without implant placement. Regeneration of a single nerve against the background of extensive hyperplasia of connective tissue

9C shows a cross-section of the spinal cord of the rat after breaking the half incision and thoracic vertebrae (T11) and placing the PTFE implant at an angle of 45 ⁰ degrees. Light gray area-PTFE. Active regeneration of nerves into the lesion area is observed.

In the experiment, a histochemical method was applied to detect cytoplasmic enzymes characterized by metabolic activity of cells, succinate and lactate dehydrogenase (LDG and SDG). The presence of enzymes in the dog's spinal cord is manifested by dark blue formazan deposits formed during the reduction of the tetrazolium salt (the main areas are the mitochondrial lining, outgoing criss, and cytoplasmic nets). Enzyme activity was evaluated by the optical density of the reaction product in the cytoplasm of the cells (Formazan) using an Image J computer data processing program, and 100 cells were considered in 5 sections.

10A-10C show cross sections of the spinal cord of mice by visualizing the activity of LDG. The presence of the enzyme is indicated in dark blue (indicated in black). (X400).

10A shows the spinal cord portion of the intact rat thoracic spine (T11).

10B shows part of the spinal cord of the rat after incision and destruction of the thoracic vertebra (T11) in half without implant placement. The LDG activity in the spinal nerve that passed through the partial incision without PTFE implantation was M ± m = 89.89 ± 17.64 (unit), which was 6.0% lower than that of the control animal and the activity of LDG enzyme in rats implanted with PTFE in the spinal incision region 11% lower.

10C shows a cross-section of the spinal cord of the rat after destruction of the half incision and thoracic vertebrae (T11) and placement of the PTFE implant at an angle of 45 ⁰ degrees. Light gray area-PTFE. The increase in LDG activity leads to activation of the glycolysis process, and consequently to the strengthening of the recovery process in the reparation process with the goal of restoring the integrity of the damaged area of the spinal cord.

11A-11C show cross sections of the spinal cord of rats by visualizing the activity of LDH. The presence of the enzyme is indicated in dark blue (indicated in black). (X400).

11A shows a spinal cord fragment of the intact rat thoracic spine (T11).

11B shows a portion of the spinal cord of the rat after incision and destruction of the thoracic vertebra (T11) in half without implant placement. The decrease in SDG activity of regenerative nerve fibers in the spinal cord in the connective tissue scar region indicates inhibition of the redox process in the Krebs cycle and a reduction in the level of energy exchange in regenerative nerve tissue. The SDG activity in the spinal nerve that passed through the partial incision without PTFE implantation was M ± m = 87,47 ± 19,22 (unit), which was 24.78% lower than the control animals and LDG of rats implanted with PTFE in the spinal incision area. The activity of the enzyme is 15.5% lower.

Figure 11c is disposed after PTFE implant in destruction and 45 ^zero-degree angle of the half-cut and the thoracic vertebrae (T11) showing the cross section of the rat spinal cord. Light gray area-PTFE.

Using the present invention, the following is possible:

One. Transplantation is performed in all periods of severe brain injury shortly after stopping a significant dysfunction and prevents or reduces the dehydration process by contributing to the initial and stable restoration of conductivity in the acute phase. Recovery of spinal cord function eliminates the harmful effects of long-term inactivity, which is of great psychological and socio-economic importance to the patient and his relatives.

2. Reduces disability due to serious spinal cord injury.

3. Improve the quality of life of the patient after severe spinal cord injury.

Thus, the present invention provides the ability to recover damaged nerve tissue in large quantities. The present invention determines if the claimed implant is suitable for treating various types of nerve tissue damage immediately after stopping the disorder and during severe nerve (especially spinal cord) tissue trauma. The present invention performs important functions to stably restore conductivity early in the acute phase and to prevent or reduce the dehydration process.

Information source

One. Yumasev Jablov, Korz et al // Orthopedic Surgeon, Traumatologist

2. Russian Patent No. 2195941 dated January 10, 2003

3. Chinese Patent No. 101653366 dated February 24, 2010

4. U.S. Patent No. 7147647 dated December 12, 2006 (Prototype)

5. Belarus Patent No. 10325 dated February 28, 2008

Claims (9)

In implants for damaged nerve tissue prostheses containing a porous material,
The porous material is a porous polytetrafluoroethylene having a surface-volume structure that is uniformly distributed on the open pores and the inner surface of the open pores and includes dead-end pores, and the pore size is randomly distributed in the range of 150-300 microns. Features of the implant
According to claim 1,
Implant characterized in that the nerve tissue is spinal cord tissue, auditory nerve or optic nerve.
According to claim 1,
Implant characterized in that the damage to the nerve tissue is the destruction or rupture of the nerve tissue, and is made in the form of a plate to replace the missing nerve tissue.
According to claim 1,
Nerve tissue damage is necrosis of the nerve tissue area. Implant characterized in that it is made in the form of a split sleeve to cover areas of necrotic nerve tissue.
A surgical treatment method for treating damaged nerve tissue, wherein an implant for prosthetic damaged nerve tissue containing a porous material is used,
The porous material is a porous polytetrafluoroethylene having a three-dimensional surface-volume structure uniformly distributed on the open pores and the inner surface of the open pores and including dead-end pores, and the pore size is randomly in the range of 150-300 microns. Method characterized by being distributed.
The method of claim 5,
A method characterized by treating damaged nerve tissue, such as spinal cord tissue, auditory nerve, or optic nerve.
The method of claim 5,
A method characterized in that the implant is made in the form of a plate and placed at the location of the missing piece of nerve tissue in order to treat damage to the nerve tissue in the form of damaged nerve tissue fragments or tissue rupture.
The method of claim 5,
A method characterized by placing the implant in the form of a split sleeve and placing it on top of the necrotic nerve tissue to treat a portion of the necrotic nerve tissue.
The porous polytetrafluoroethylene according to claim 1 is used to prepare an implant for prosthesis of damaged nerve tissue.

Images